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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1563-1564
Hypoxia-inducible factors and marrow stromal function
Multicellular organisms have developed complex organ systems for the
uptake, transport, and delivery of oxygen. Many processes involved in oxygen
homeostasis are mediated by hypoxia-inducible factors (HIFs), which control
the transcription of a number of target genes. Initially identified as the key
regulators of the erythropoietin gene, HIFs have subsequently been shown to
participate in the control of a wide array of oxygen-regulated
genes.
The HIF transcriptional complex is a heterodimer consisting of an alpha
subunit (HIF-1 , HIF-2, or HIF-3) and a beta subunit
called ARNT (arylhydrocarbon receptor nuclear translocator). During hypoxia
the HIF complex up-regulates the expression of a number of genes involved in
erythropoiesis, angiogenesis, vasomotor control, and energy metabolism by
binding to a hypoxia-response element in target genes. The regulation of
HIF-complex activity is primarily at the level of HIF alpha subunit protein
stability. While the ARNT subunit is not affected by hypoxia, HIF-1 and
HIF-2 proteins accumulate under hypoxic conditions and are rapidly
degraded under normoxic conditions. The cellular oxygen sensor underlying this
regulation resides in a number of prolyl hydroxylase enzymes (designated PHDs)
which, under normoxic conditions, hydroxylate critical residues on the
HIF- subunit. These modifications serve as signals for binding to the
von Hippel-Lindau (VHL) protein that facilitates HIF- ubiquitination
and subsequent degradation via the proteosome pathway.
What then do the HIFs have to do with hematopoiesis? Previous studies
showed that hypoxia induces a significant increase in colony-forming units
(CFUs) derived from human bone marrow (see Maeda et al, Exp Hematol.
1986;14:930-934). More recently, Adelman et al (Genes & Dev. 1999;13:
2478-2483) showed that wild-type but not ARNT null embryoid bodies showed
increased CFUs in response to hypoxia. In addition, they found that ARNT null
embryos had decreased numbers of yolk sac hematopoietic progenitors. To
determine whether this defect was intrinsic to hematopoietic progenitors,
Adelman and colleagues generated chimeric mice by injecting wild-type or ARNT
null embryonic stem (ES) cells into normal blastocysts and assaying CFU
formation in adult marrow. As in the wild-type control, the number of ARNT
null CFUs correlated with the percent chimerism of each animal, indicating a
defect extrinsic to the hematopoietic progenitors. ARNT null embryoid bodies
had a markedly decreased production of vascular endothelial growth factor
(VEGF) when cultured in hypoxic conditions. Addition of exogenous VEGF to ARNT
null embryoid bodies restored CFU numbers to normal. Together, these studies
suggested that embryonic hematopoiesis requires hypoxic ARNT activity and that
physiologic hypoxia encountered by embryos is essential for the proliferation
or survival of hematopoietic precursors during development. These studies did
not determine whether HIF-1 or HIF-2 were necessary for this
ARNT activity.
In the current issue, Scortegagna and colleagues (page
1634) have shown that
HIF-2 (also known as endothelial PAS domain protein 1 [EPAS1]) is
essential for normal hematopoiesis in mice. They generated viable adult
EPAS1/HIF-2 null mice that were pancytopenic with hypocellular marrows.
Multilineage hematopoietic maturation was normal but quantitatively reduced.
Bone marrow from EPAS1/HIF-2 null mice functioned normally when
transplanted into irradiated wild-type recipients. In contrast,
transplantation of wild-type marrow into irradiated EPAS1/HIF-2 null
recipients resulted in impaired hematopoietic reconstitution, indicating a
defect in the marrow microenvironment. Interestingly, levels of VEGF and VEGF
receptor mRNA in marrow from EPAS1/HIF-2 null mice did not differ from
that of wild-type mice. On the other hand, expression of mRNA for a number of
cell surface proteins, including vascular cell adhesion molecule 1 (VCAM-1),
urokinase-type plasminogen activator receptor (uPAR), and fibronectin, were
substantially altered in marrow from EPAS1/HIF-2 null mice. These
studies reinforce both the importance of the HIF transcriptional complex in
hematopoiesis and its function in providing the necessary marrow
microenvironment for effective hematopoiesis. The different role of VEGF in
embryonic and adult hematopoiesis is puzzling and may relate to a greater
degree of hypoxia found in the embryonic hematopoietic compartment or be
intrinsic to embryonic versus adult hematopoietic progenitors. Additional
studies will be required to define whether EPAS1/HIF-2 is the ARNT
partner required for embryonic as well as adult hematopoiesis. This study
provides important insights into marrow stromal cell biology and opens
potential avenues of exploration both into the role of stroma in marrow
failure syndromes and into novel ways to support and expand hematopoietic
progenitors in vitro.
Peter T. Curtin
Oregon Health & Science University
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